Project Summary/Abstract The ability to update strategies as contingencies change, or cognitive flexibility, is a fundamental behavioral process that allows for maximizing positive, while minimizing aversive, outcomes. This process is critical for survival, and its dysregulation is a hallmark of a number neuropsychiatric disorders including addiction. For example, cocaine addicts have a slowed ability to learn new associations, and also make risky choices despite environmental cues indicating that more advantageous choices are available. These deficits are similar to those seen in patients with damage to prefrontal cortical areas, and imagining studies in cocaine addicts also suggests that cocaine-induced plasticity in medial prefrontal cortex (mPFC) may be involved. While hypotheses as to the circuit basis of cocaine-induced cognitive deficits have been generated from clinical studies, in many cases we lack direct, mechanistic preclinical data verifying these hypotheses. In our preliminary studies in rats we have identified two projection-defined subpopulations in the mPFC, cells that project to the nucleus accumbens or those that project to the periaqueductal gray area, which divergently encode positive and negative stimuli. We hypothesize that these populations are involved in cognitive flexibility, and its dysregulation by cocaine. The experiments put forth in this proposal will systematically test this hypothesis by combining single-cell calcium imaging, to record endogenous activity, and optogenetics, to manipulate activity, with intravenous cocaine self- administration. The cutting-edge technologies employed in this proposal will allow us to test the novel hypothesis that specific subpopulations in the mPFC are critically involved in fundamental behavioral control, cognitive flexibility, and cocaine-induced deficits in these processes. A successful outcome of this proposal will facilitate my transition to an independent academic position, while advancing our understanding of the circuit basis of cocaine addiction.